Proprioceptive acuity for landmarks on the hand and digits.

Previous work using visually guided reaches to localize landmarks on a hidden hand has suggested that proprioceptive acuity for hand targets is low and representation of hand dimensions is highly distorted (e.g., hand width estimated to be 60% wider than actual hand width). We re-examined these issues using a pure proprioceptive task in which 20 blindfolded subjects reached in a single movement without terminal corrections to touch the right index-tip to landmarks of the left hand placed in various locations in 3D space. Subjects were also tested with vision allowed to estimate minimal errors. Based on previous reports of high proprioceptive acuity for some hand landmarks, we hypothesized that the proprioceptive representation of the hand was much less distorted than described previously and that errors were not correlated with target hand location. Mean distance errors in proprioceptively guided reaches to the landmarks averaged less than 3 cm and were only 0.5-1.3 cm larger than when vision was allowed. Errors were not correlated with hand location in most subjects. Distortions of hand width averaged less than 20% wider than actual width and were not correlated with hand location in most subjects. We conclude that relatively accurate proprioceptive awareness of locations of hand/digit structures and dimensions is available for use in control of hand movements, which are executed largely subconsciously. Studying acuity of proprioception using conscious perceptual tasks and involving vision may not provide accurate measures of proprioceptive acuity as used by the motor system.

More than fear: Contributions of biobehavioral synchrony and infants' reactivity to cooperative care.

We present two challenges to the fearful ape hypothesis: (1) biobehavioral synchrony precedes and moderates the effects of fear on cooperative care, and (2) cooperative care emerges in a more bidirectional manner than Grossmann acknowledges. We present evidence demonstrating how dyadic differences in co-regulation and individual differences in infants' reactivity shape caregivers' responses to infant affect.

High proprioceptive acuity in slow and fast hand movements.

We can accurately reach to touch our index fingertip to various points on the body without vision. Awareness of location/motion of the index fingertip and other body parts through proprioception is required for such movements. Proprioception involves processing sensory information, but it is also debated whether internal model estimates of body state from motor commands improve proprioception. We tested the hypothesis that proprioceptive errors increase with increases in speed of hand movement and whether an internal model contributes to more accurate proprioception, especially in higher speed movements. Ten subjects made voluntary reaching movements with their dominant arm to touch its index-tip to the index-tip of the non-dominant arm that was moved passively or actively at three speeds (slow, comfortable, fast) in various directions. Four conditions required the experimenter to passively move the subject's target arm at slow, comfortable and fast speeds and in different directions. A fifth condition required the subject to actively move both arms to perform the task. Subjects performed these tasks with high accuracy during slow and comfortable speed movements of the target arm. Errors averaged 3.7 mm larger when the target was moved faster and were equivalent to errors for slower movements (p < 0.014). Errors in the active and passive target movement conditions were also equivalent (p < 0.001). These findings show that proprioception is accurate across many different speeds of passive and active target motion and that there was no evidence than an internal model contributes to improved accuracy of proprioception during active movements.

Associations between acoustic features of maternal speech and infants' emotion regulation following a social stressor.

Caregiver voices may provide cues to mobilize or calm infants. This study examined whether maternal prosody predicted changes in infants' biobehavioral state after the still face, a stressor in which the mother withdraws and reinstates social engagement. Ninety-four dyads participated in the study (infant age 4-8 months). Infants' heart rate and respiratory sinus arrhythmia (measuring cardiac vagal tone) were derived from an electrocardiogram (ECG). Infants' behavioral distress was measured by negative vocalizations, facial expressions, and gaze aversion. Mothers' vocalizations were measured via a composite of spectral analysis and spectro-temporal modulation using a two-dimensional fast Fourier transformation of the audio spectrogram. High values on the maternal prosody composite were associated with decreases in infants' heart rate (ß = -.26, 95% CI: [-0.46, -0.05]) and behavioral distress (ß = -.23, 95% CI: [-0.42, -0.03]), and increases in cardiac vagal tone in infants whose vagal tone was low during the stressor (1 SD below mean ß = .39, 95% CI: [0.06, 0.73]). High infant heart rate predicted increases in the maternal prosody composite (ß = .18, 95% CI: [0.03, 0.33]). These results suggest specific vocal acoustic features of speech that are relevant for regulating infants' biobehavioral state and demonstrate mother-infant bi-directional dynamics.

Proximity and touch are associated with neural but not physiological synchrony in naturalistic mother-infant interactions.

Caregiver touch plays a vital role in infants' growth and development, but its role as a communicative signal in human parent-infant interactions is surprisingly poorly understood. Here, we assessed whether touch and proximity in caregiver-infant dyads are related to neural and physiological synchrony. We simultaneously measured brain activity and respiratory sinus arrhythmia of 4-6-month-old infants and their mothers (N=69 dyads) in distal and proximal joint watching conditions as well as in an interactive face-to-face condition. Neural synchrony was higher during the proximal than during the distal joint watching conditions, and even higher during the face-to-face interaction. Physiological synchrony was highest during the face-to-face interaction and lower in both joint watching conditions, irrespective of proximity. Maternal affectionate touch during the face-to-face interaction was positively related to neural but not physiological synchrony. This is the first evidence that touch mediates mutual attunement of brain activities, but not cardio-respiratory rhythms in caregiver-infant dyads during naturalistic interactions. Our results also suggest that neural synchrony serves as a biological pathway of how social touch plays into infant development and how this pathway could be utilized to support infant learning and social bonding.

Associations between infant-mother physiological synchrony and 4- and 6-month-old infants' emotion regulation.

In this study we assessed whether physiological synchrony between infants and mothers contributes to infants' emotion regulation following a mild social stressor. Infants between 4 and 6 months of age and their mothers were tested in the face-to-face-still-face paradigm and were assessed for behavioral and physiological self-regulation during and following the stressor. Physiological synchrony was calculated from a continuous measure of respiratory sinus arrhythmia (RSA) enabling us to cross-correlate the infants' and mothers' RSA responses. Without considering physiological synchrony, the evidence suggested that infants' distress followed the prototypical pattern of increasing during the Still Face episode and then decreasing during the reunion episode. Once physiological synchrony was added to the model, we observed that infants' emotion regulation improved if mother-infant synchrony was positive, but not if it was negative. This result was qualified further by whether or not infants suppressed their RSA response during the Still Face episode. In sum, these findings highlight how individual differences in infants' physiological responses contribute significantly to their self-regulation abilities.

Contemporary pollen-mediated gene immigration reflects the historical isolation of a rare, animal-pollinated shrub in a fragmented landscape.

Fragmentation is generally considered to have negative impacts on widespread outbreeders but impacts on gene flow and diversity in patchy, naturally rare, self-compatible plant species remain unclear. We investigated diversity, gene flow and contemporary pollen-mediated gene immigration in the rare, narrowly distributed endemic shrub Calothamnus quadrifidus ssp. teretifolius. This taxon occurs in an internationally recognized biodiversity hotspot subjected to recent human-induced fragmentation and the condition of the remnants ranges from intact to highly degraded. Using microsatellites, we found that inbreeding, historically low gene flow and significant population differentiation have characterized the genetic system of C. quadrifidus ssp. teretifolius. Inbreeding arises from self-pollination, a small amount of biparental inbreeding and significant correlation of outcross paternity but fecundity was high suggesting populations might have purged their lethals. Paternity analyses show that pollinators can move pollen over degraded and intact habitat but populations in both intact and degraded remnants had few pollen parents per seed parent and low pollen immigration. Genetic diversity did not differ significantly between intact and degraded remnants but there were signs of genetic bottlenecks and reduced diversity in some degraded remnants. Overall, our study suggests human-induced fragmentation has not significantly changed the mating system, or pollen immigration to, remnant populations and therefore genetic connectivity need not be the highest conservation priority. Rather, for rare species adapted to higher levels of inbreeding, conservation efforts may be best directed to managing intact habitats and ecosystem processes.

The insufficiency of associative learning for explaining development: three challenges to the associative account.

Three challenges to the sufficiency of the associative account for explaining the development of mirror mechanisms are discussed: Genetic predispositions interact with associative learning, infants show predispositions to imitate human as opposed to nonhuman actions, and early and later learning involve different mechanisms. Legitimate objections to an extreme nativist account are raised, but the proposed solution is equally problematic.

Differential contributions of development and learning to infants' knowledge of object continuity and discontinuity.

Sixty infants divided evenly between 5 and 7 months of age were tested for their knowledge of object continuity versus discontinuity with a predictive tracking task. The stimulus event consisted of a moving ball that was briefly occluded for 20 trials. Both age groups predictively tracked the ball when it disappeared and reappeared via occlusion, but not when it disappeared and reappeared via implosion. Infants displayed high levels of predictive tracking from the first trial in the occlusion condition, and showed significant improvement across trials in the implosion condition. These results suggest that infants possess embodied knowledge to support differential tracking of continuously and discontinuously moving objects, but this tracking can be modified by visual experience.

How attention factors into executive function in preschool children.

Executive Function consists of self-regulation processes which underlie our ability to plan, coordinate, and complete goal-directed actions in our daily lives. While attention is widely considered to be central to the emergence and development of executive function during early childhood, it is not clear if it is integral or separable from other executive function processes. Previous studies have not addressed this question satisfactorily because executive function and attention are multidimensional constructs, but they are often studied without differentiating the specific processes that are tested. Moreover, some studies consist of only one task per process, making it difficult to ascertain if the pattern of results is attributable to different processes or more simply to task variance. The main aim of this study was to more fully investigate how attention factored into the underlying structure of executive function in preschool children. Preschool children (n = 137) completed a battery of tasks which included executive function (i.e., response inhibition, working memory) and attentional control (i.e., sustained attention, selective attention) processes; there were two tasks per process. Confirmatory factor analyses (CFA) were conducted to test which of three models fit the data best: (1) a unitary one-factor model with attention loading onto the same factor as other executive function processes, (2) a two-factor model with attention loading onto a separate factor than other executive function processes, or (3) a three-factor model with attention, response inhibition, and working memory as separate factors. Fit indices and model comparisons indicated that the two-factor model fit the data best, suggesting that attentional control and executive function were related, but separable. Although this study is not the first to advocate for a two-factor model during the preschool years, it is the first to suggest that the two factors are attentional control and executive function, not working memory and response inhibition. One important implication of these findings is that a complete assessment of executive function during the preschool years necessitates measuring not only response inhibition and working memory, but attentional control as well.

Dynamic pointing triggers shifts of visual attention in young infants.

Pointing, like eye gaze, is a deictic gesture that can be used to orient the attention of another person towards an object or an event. Previous research suggests that infants first begin to follow a pointing gesture between 10 and 13 months of age. We investigated whether sensitivity to pointing could be seen at younger ages employing a technique recently used to show early sensitivity to perceived eye gaze. Three experiments were conducted with 4.5- and 6.5-month-old infants. Our first goal was to examine whether these infants could show a systematic response to pointing by shifting their visual attention in the direction of a pointing gesture when we eliminated the difficulty of disengaging fixation from a pointing hand. The results from Experiments 1 and 2 suggest that a dynamic, but not a static, pointing gesture triggers shifts of visual attention in infants as young as 4.5 months of age. Our second goal was to clarify whether this response was based on sensitivity to the directional posture of the pointing hand, the motion of the pointing hand, or both. The results from Experiment 3 suggest that the direction of motion is necessary but not sufficient to orient infants' attention toward a distal target. Infants shifted their attention in the direction of the pointing finger, but only when the hand was moving in the same direction. These results suggest that infants are prepared to orient to the distal referent of a pointing gesture which likely contributes to their learning the communicative function of pointing.

Coupling between prefrontal brain activity and respiratory sinus arrhythmia in infants and adults.

Self-regulation is an essential aspect of healthy child development. Even though infants depend on their caregivers for co-regulation during the first years, they begin to gain regulatory abilities through social interactions as well as their own developing agency and inhibitory control. These early regulatory abilities continue to increase with the development of both the prefrontal cortex and the vagal system. Importantly, theoretical accounts have suggested that the prefrontal cortex and the vagal system are linked through forward and backward feedback loops via the limbic system. Decreased coupling within this link is suggested to be associated with psychopathology. The primary goal of this study was to examine whether intrapersonal coupling of prefrontal brain activity and respiratory sinus arrhythmia is evident in infancy. Using the simultaneous assessment of functional near-infrared spectroscopy and electrocardiography, we used Cross-Recurrence Quantification Analysis to assess the coupling of prefrontal brain activity and respiratory sinus arrhythmia in 69 4- to 6-month-old infants and their mothers during a passive viewing condition. However, we did not find significant coupling between the PFC and RSA in infants and adult caregivers. Future studies could examine social contexts associated with greater emotional reactivity to deepen our understanding of the pathways involved in self-regulation.

Coupling between prefrontal brain activity and respiratory sinus arrhythmia in infants and adults.

Self-regulation is an essential aspect of healthy child development. Even though infants are dependent on their caregivers for co-regulation during the first years, they begin to gain early regulatory abilities through social interactions as well as their own cognitive development. These early regulatory abilities continue to increase with the maturation of both the prefrontal cortex and the vagal system. Importantly, theoretical accounts have suggested that the prefrontal cortex and the vagal system are linked through forward and backward feedback loops via the limbic system. Decreased coupling within this link is suggested to be associated with psychopathology. The primary goal of this study is to examine whether intrapersonal coupling of prefrontal brain activity and respiratory sinus arrythmia is evident in infancy. Using the simultaneous assessment of functional near-infrared spectroscopy and electrocardiography, we will use Cross-Recurrence Quantification Analysis to assess the coupling of prefrontal brain activity and respiratory sinus arrhythmia in 69 4-6-month-old infants and their mothers during rest. Understanding the developmental emergence of the neurobiological correlates of self- regulation will allow us to help identify neurodevelopmental risk factors.

An interactionist perspective on the development of coordinated social attention.

Infants' ability to coordinate their attention with other people develops profoundly across the first year of life. Mainly based on experimental research focusing on infants' behavior under highly controlled conditions, developmental milestones were identified and explained in the past by prominent theories in terms of the onset of specific cognitive skills. In contrast to this approach, recent longitudinal research challenges this perspective with findings suggesting that social attention develops continuously with a gradual refinement of skills. Informed by these findings, we argue for an interactionist and dynamical systems view that bases observable advances in infant social attention skills on increasingly fine-tuned mutual adjustments in the caregiver-infant dyad, resulting in gradually improving mutual prediction. We present evidence for this view from recent studies leveraging new technologies which afford the opportunity to dynamically track social interactions in real-time. These new technically-sophisticated studies offer unprecedented insights into the dynamic processes of infant-caregiver social attention. It is now possible to track in much greater detail fluctuations over time with regard to object-directed attention as well as social attention and how these processes relate to one another. Encouraged by these initial results and new insights from this interactionist developmental social neuroscience approach, we conclude with a "call to action" in which we advocate for more ecologically valid paradigms for studying social attention as a dynamic and bi-directional process.

Intrapatient comparisons of efficacy in a single-arm trial of entrectinib in tumour-agnostic indications.

BACKGROUND: Entrectinib is a tropomyosin receptor kinase inhibitor approved for the treatment of neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours based on single-arm trials. Traditional randomised clinical trials in rare cancers are not feasible; we conducted an intrapatient analysis to evaluate the clinical benefit of entrectinib versus prior standard-of-care systemic therapies. METHODS: Patients with locally advanced/metastatic NTRK fusion-positive tumours enrolled in the global phase II, single-arm STARTRK-2 trial were grouped according to prior systemic therapy and response. The key analysis used growth modulation index [GMI; ratio of progression-free survival (PFS) on entrectinib to time to discontinuation (TTD) on the most recent prior therapy]; ratio ≥1.3 indicated clinically meaningful efficacy. Additional analyses investigated TTD and objective response rate (ORR) for entrectinib and prior therapies. RESULTS: Seventy-one patients were included; 51 received prior systemic therapy. In 38 patients who progressed on prior therapy, ORR was 60.5% (23/38) with entrectinib and 15.8% (6/38) with the most recent prior therapy. Median PFS [11.2 months; 95% confidence interval (CI) 6.7-not estimable] for entrectinib exceeded median TTD (2.9 months; 95% CI 2.0-4.9) for most recent prior therapy. From the intrapatient analysis of GMI, 65.8% had a ratio ≥1.3 and median GMI was 2.53. Consistent results were observed at more stringent GMI thresholds; 60.5% of patients had GMI ≥1.5 or ≥1.8 and 57.9% had GMI ≥2.0. CONCLUSIONS: ORR was high and PFS was longer on entrectinib versus TTD on prior therapy. Furthermore, 65.8% of patients experienced clinically meaningful benefit based on GMI. This intrapatient analysis demonstrates comparative effectiveness of entrectinib in a rare, heterogeneous adult population.

A method for measuring dynamic respiratory sinus arrhythmia (RSA) in infants and mothers.

The measurement of respiratory sinus arrythmia (RSA) in infants, children and adults is critical to the study of physiological regulation, and more recently, interpersonal physiological covariation, but it has been impeded by methods that limit its resolution to 30 s or longer. Recent analytical developments have suggested methods for studying dynamic RSA in adults, and we have extended this work to the study of infants and mothers. In the current paper, we describe a new analytical strategy for estimating RSA time series for infants and adults. Our new method provides a means for studying physiological synchrony in infant-mother dyads that offers some important advantages relative to existing methods that use inter-beat-intervals (e.g. Feldman, Magori-Cohen, Galili, Singer, & Louzoun, 2011). In the middle sections of this paper, we offer a brief tutorial on calculating RSA continuously with a sliding window and review the empirical evidence for determining the optimal window size. In order to confirm the reliability of our results, we briefly discuss testing synchrony by randomly shuffling the dyads to control for spurious correlations, and also by using a bootstrapping technique for calculating confidence intervals in the cross-correlation function. One important implication that emerges from applying this method is that it is possible to measure both positive and negative physiological synchrony and that these categorical measures are differentially predictive of future outcomes.

Definition of a natural killer NKR-P1A+/CD56-/CD16- functionally immature human NK cell subset that differentiates in vitro in the presence of interleukin 12.

Human natural killer (NK) cell differentiation from immature lineage negative (Lin-) umbilical cord blood cells was examined in vitro. Cells expressing differentiation antigens of mature NK cells (CD56, CD16, CD2, CD8, NKR-P1A) were generated from Lin- cells cultured with interleukin (IL)-2 and a murine bone marrow stromal cell line expressing the human membrane-bound form of stem cell factor. Two subsets of NK cells were identified in these cultures: one expressed both NKR-P1A and CD56 and, in variable proportions, all other NK cell differentiation antigens; the second subset expressed only NKR-P1A and, unlike the former, was not cytotoxic. Neither subset expressed interferon (IFN)-gamma mRNA even after stimulation with phorbol di-ester and Ca2+ ionophore, but both expressed tumor necrosis factor alpha mRNA and the cytotoxic granule-associated proteins TIA-1, perforin, and serine esterase-1. After 10-d culture with IL-2, IL-12, and irradiated B lymphoblastoid cells, approximately 45% of the NKR-P1A+/ CD56- cells became CD56+, and the same cultures contained cells capable of cytotoxicity and of IFN-gamma production. These results indicate that NKR-P1A expression in the absence of other NK cell markers defines an intermediate, functionally immature stage of NK cell differentiation, and that effector functions develop in these cells, concomitantly with CD56 expression, in the presence of IL-12. These cells likely represent the counterpart of a CD3-/NKR-P1A+/ CD56-/CD16- cell subset that, as shown here, is present both in adult and neonatal circulating lymphocytes.

Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells.

Mature natural killer (NK) cells use Ca2+-dependent granule exocytosis and release of cytotoxic proteins, Fas ligand (FasL), and membrane-bound or secreted cytokines (tumor necrosis factor [TNF]-alpha) to induce target cell death. Fas belongs to the TNF receptor family of molecules, containing a conserved intracytoplasmic "death domain" that indirectly activates the caspase enzymatic cascade and ultimately apoptotic mechanisms in numerous cell types. Two additional members of this family, DR4 and DR5, transduce apoptotic signals upon binding soluble TNF-related apoptosis-inducing ligand (TRAIL) that, like FasL, belongs to the growing TNF family of molecules. Here, we report that TRAIL produced or expressed by different populations of primary human NK cells is functional, and represents a marker of differentiation or activation of these, and possibly other, cytotoxic leukocytes. During differentiation NK cells, sequentially and differentially, use distinct members of the TNF family or granule exocytosis to mediate target cell death. Phenotypically immature CD161(+)/CD56(-) NK cells mediate TRAIL-dependent but not FasL- or granule release-dependent cytotoxicity, whereas mature CD56(+) NK cells mediate the latter two.

The temporal dynamics of infants' joint attention: Effects of others' gaze cues and manual actions.

Infants' development of joint attention shows significant advances between 9 and 12 months of age, but we still need to learn much more about how infants coordinate their attention with others during this process. The objective of this study was to use eye tracking to systematically investigate how 8- and 12-month-old infants as well as adults dynamically select their focus of attention while observing a social partner demonstrate infant-directed actions. Participants were presented with 16 videos of actors performing simple infant-directed actions from a first-person perspective. Looking times to faces as well as hands-and-objects were calculated for participants at each age, and developmental differences were observed, although all three groups looked more at hands-and-objects than at faces. In order to assess whether visual attention was coordinated with the actors' behaviors, we compared participants looking at faces and objects in response to gaze direction as well as infant-directed actions vs. object-directed actions. By presenting video stimuli that involved continuously changing actions, we were able to document that the likelihood of joint attention changes in both real and developmental time. Overall, adults and 12-month-old infants' visual attention was modulated by gaze cues as well as actions, whereas this was only partially true for 8-month-old infants. Our results reveal that joint attention is not a monolithic process nor does it develop all at once.

Physalia nematocysts: utilized by mollusks for defense.

Nudibranchs Glaucus and Glaucilla store and utilize for their own defense the nematocysts of the venomous siphonophore Physalia.